DESCRIPTION (Adapted from the application): Combinatorial synthetic methods will serve as the basis for developing novel silane-containing camptothecins (silatecans) and related camptothecins with optimized biological performance. The applicant will combine the power of parallel synthesis with recent innovations by Dr. Curran's lab in camptothecin synthetic methods to generate highly potent, blood-stable, and efficacious anticancer drugs. The applicant intends to overcome the marginalization of the activities of existing alpha-hydroxy delta-lactone camptothecins caused by the hydrolysis at physiological pH of the lactone pharmacophore, resulting in the formation of an inactive carboxylate species. For several camptothecins (e.g., 9-aminocamptothecin, 9-nitrocamptothecin), the hydrolysis reaction and the ability of human albumin to bind avidly the resulting carboxylate forms leads to a rapid and essentially complete ring opening in patient blood. Further complicating their clinical utilization is the inappropriateness of animal model data; the active lactone forms are present in some 100-fold greater amounts in mouse blood vs. human blood due to the high, species-specific binding of carboxylate forms to human albumin. The applicant will provide evidence that combined modifications in the A, B and E rings of camptothecins markedly stabilizes the lactone forms in human blood. Small quantities (3 to 10 mg) of approximately 100 novel E-ring modified analogs will be synthesized. Lead candidates displaying high intrinsic potency against topoisomerase I, high cytotoxic potencies against cancer cells in vitro, and excellent human and animal blood stabilities with insignificant interspecies variations, will be resynthesized and advanced to in vivo efficacy evaluation in mice bearing human tumors. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE